Objective: To describe an uncommon movement disorder phenotype of Alexander disease (AD).

Background: AD is a rare autosomal dominant disorder that causes progressive leukodystrophy, especially in the frontal lobes. Mutations in the gene coding for glial fibrillary acidic protein (GFAP) are found in all variants of AD. Rosenthal fibers in astrocytes of brain and spinal cord are the morphologic hallmark of AD. There are MRI criteria for diagnosis of AD, but genetic testing has become the preferred diagnostic modality. There are three clinical variants of AD: infantile, juvenile, and adult onset forms. The infantile form typically manifests as rapidly progressive macrocephaly and seizures; the juvenile form has a slower progression, with bulbar signs, ataxia, spasticity, and ocular motor abnormalities; and the adult form frequently presents with ataxia, ocular motor abnormalities, and palatal myoclonus.

Methods: This 35-year-old woman presented with progressive difficulty walking and using her left hand. She has had progressive vision loss since age 8, with retinal features of classic retinitis pigmentosa, and progressive ophthalmoparesis. She has also had personality and cognitive changes. She was found to have a right frontal mass and porencephalic cyst, which were resected. At that time, a histopathologic diagnosis of pilocytic astrocytoma (PA), WHO grade I was rendered. Serial brain MRIs showed variable enhancement in the left middle cerebellar peduncle, hypothalamus, and thalamus. On examination, she had spastic ataxic gait and dystonic posturing of the left arm and leg. She has been repeatedly treated with botulinum toxin injections for hemidystonia, with moderate improvement.

Results: Whole exome sequencing (WES) revealed a heterozygous c.989G>C (p.R330P) novel variant of uncertain significance (VUS) in the GFAP gene. Another change in the same amino acid (Arg330Gly) has been described in another family with AD. The “frontal tumor and cyst wall” pathology slides when re-examined, showed profuse Rosenthal fiber formation in astrocytes and, in addition, distinctive Rosenthal fiber-like granular inclusions in astrocytic cell bodies, characteristic of AD and not seen in PA.  While WES showed a VUS, it is thought to be causative of her disease given her phenotype and histologic features. Hence, the diagnosis was changed from PA to AD.

Conclusions: This case of hemidystonia broadens the spectrum of movement disorders in AD beyond ataxia and palatal myoclonus.

References:

1. Van Poppel K, Broniscer A, Patay Z, Morris EB. Alexander disease: An important mimicker of focal brainstem glioma. Pediatr Blood Cancer. 2009;53(7):1355-6.
2. Balbi, P., Salvini, S., Fundarò, C. et al. Adult-onset Alexander disease : report on a family. J Neurol. 2010;257,(12), 1955–1962.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/hemidystonia-associated-with-alexander-disease/